Certain compounds of low toxicity have been discovered to bind to specific molecular recognition sites (drug receptor or neurotransmitter receptor sites) within tissue. The primary area in which these discoveries have occurred has been the brain due to the high population and diversity of such sites within nervous tissue although such sites are present throughout the body. Awareness of receptor sites in the body has emerged from pharmacological studies originally intended to discover the bases of action for drugs empirically found to be useful in the treatment of various disorders. It is believed that many disorders, particularly those of the nervous system, are due to altered activity in various receptor populations. Through study of the regional distribution and activity of these varied receptor systems a picture of tissue function can be derived. The initial step in any such study involves the selection of compounds which will selectively interact with the sites of interest.
One neurotransmitter-receptor system of interest is the dopaminergic system. The relationship of the activity of this system to psychopathological symptoms is not entirely clear, however, its importance is inferred through the effectiveness of dopamine receptor antagonists in abating psychotic symptoms. A number of compounds of different classes have this desired effect and would lend themselves to adaptation for study of their sites of activity. These would include drugs of the butyrophenone class such as spiperone, haloperidol (Haldol) and droperidol; drugs of the phenothiazine class such as trifluoperazine and thiothixene; and drugs of the benzamide class such as sulpiride. Alternatively, dopamine receptor agonists, such as bromocriptine, might serve as useful ligand substrates for study of the dopaminergic system, particularly among individuals suffering from parkinsonism.
The term "ligand" is used herein to generally describe the tissue binding portion of the active molecules referred to above. It can be seen that for the most part the molecules are psychoactive drugs. However, from time to time the broader term "ligand" is used because many of the useful compounds may well be derived from psychoactive drugs, but they themselves may not be the active drug form.
Pharmacological, biochemical and behavioral characterization of sigma binding sites is currently the focus of intense, wide-spread investigation. While the precise nature of sigma binding sites in cells is not quite known, many studies have suggested that it represents the site of action for a number of important drugs. For example, haloperidol, a butyrophenone antipsychotic, exhibits high affinity for sigma binding sites and several psychotominetics, including PCP and benzomorphane, also bind at this site. Thus, strong binding sigma agents are indicative of usefulness in the treatment of schizophrenia.
In fact, several sigma compounds have been developed as antipsychotics. It is also believed that strong sigma site binding may also indicate therapeutic targets for epilepsy and brain ischemia.
In sum, the discovery of sigma binding sites has prompted investigation into the functional role of the sites. While the functional role is not precisely understood, it is nevertheless true that binding studies have revealed sigma sites which may exhibit a unique pharmacological profile, and have provided evidence favoring the existence of a multiplicity of sigma binding sites in the central nervous system. There is therefore a continuing investigation and search for psychoactive compounds having a strong affinity for sigma binding sites.
This invention has as its primary objective the development of new psychoactive drugs having a high degree of binding affinity at sigma binding sites and which by the nature of the chemical structure have little or no likelihood of significant side affects. These compounds are thus highly useful antipsychotic drugs for treatments of certain mental disorders such as schizophrenia.